The present invention relates to processing, storage, transport and delivery containers for hyperpolarized noble gases.
Conventionally, Magnetic Resonance Imaging (xe2x80x9cMRIxe2x80x9d) has been used to produce images by exciting the nuclei of hydrogen molecules (present in water protons) in the human body. However, it has recently been discovered that polarized noble gases can produce improved images of certain areas and regions of the body which have heretofore produced less than satisfactory images in this modality. Polarized Helium-3 (xe2x80x9c3Hexe2x80x9d) and Xenon-129 (xe2x80x9c129Xexe2x80x9d) have been found to be particularly suited for this purpose. Unfortunately, as will be discussed further below, the polarized state of the gases are sensitive to handling and environmental conditions and, undesirably, can decay from the polarized state relatively quickly.
Hyperpolarizers are used to produce and accumulate polarized noble gases. Hyperpolarizers artificially enhance the polarization of certain noble gas nuclei (such as 129Xe or 3He) over the natural or equilibrium levels, i.e., the Boltzmann polarization. Such an increase is desirable because it enhances and increases the MRI signal intensity, allowing physicians to obtain better images of the substance in the body. See U.S. Pat. No. 5,545,396 to Albert et al., the disclosure of which is hereby incorporated herein by reference as if recited in full herein.
In order to produce the hyperpolarized gas, the noble gas is typically blended with optically pumped alkali metal vapors such as rubidium (xe2x80x9cRbxe2x80x9d). These optically pumped metal vapors collide with the nuclei of the noble gas and hyperpolarize the noble gas through a phenomenon known as xe2x80x9cspin-exchangexe2x80x9d. The xe2x80x9coptical pumpingxe2x80x9d of the alkali metal vapor is produced by irradiating the alkali-metal vapor with circularly polarized light at the wavelength of the first principal resonance for the alkali metal (e.g., 795 nm for Rb). Generally stated, the ground state atoms become excited, then subsequently decay back to the ground state. Under a modest magnetic field (10 Gauss), the cycling of atoms between the ground and excited states can yield nearly 100% polarization of the atoms in a few microseconds. This polarization is generally carried by the lone valence electron characteristics of the alkali metal. In the presence of non-zero nuclear spin noble gases, the alkali-metal vapor atoms can collide with the noble gas atoms in a manner in which the polarization of the valence electrons is transferred to the noble-gas nuclei through a mutual spin flip xe2x80x9cspin-exchangexe2x80x9d.
After the spin-exchange has been completed, the hyperpolarized gas is separated from the alkali metal prior to introduction into a patient to form a non-toxic or sterile composition. Unfortunately, during and after collection, the hyperpolarized gas can deteriorate or decay (lose its hyperpolarized state) relatively quickly and therefore must be handled, collected, transported, and stored carefully. The xe2x80x9cT1xe2x80x9d decay constant associated with the hyperpolarized gas""s longitudinal relaxation time is often used to describe the length of time it takes a gas sample to depolarize in a given container. The handling of the hyperpolarized gas is critical, because of the sensitivity of the hyperpolarized state to environmental and handling factors and the potential for undesirable decay of the gas from its hyperpolarized state prior to the planned end use, i.e., delivery to a patient. Processing, transporting, and storing the hyperpolarized gasesxe2x80x94as well as delivery of the gas to the patient or end userxe2x80x94can expose the hyperpolarized gases to various relaxation mechanisms such as magnetic gradients, ambient and contact impurities, and the like.
Typically, hyperpolarized gases such as 129Xe and 3He have been collected in relatively pristine environments and transported in specialty glass containers such as rigid Pyrex(trademark) containers. However, to extract the majority of the gas from these rigid containers, complex gas extraction means are typically necessary. Hyperpolarized gas such as 3He and 129Xe has also been temporarily stored in single layer resilient Tedlar(copyright) and Teflon(copyright) bags. However, these containers have produced relatively short relaxation times.
One way of inhibiting the decay of the hyperpolarized state is presented in U.S. Pat. No. 5,612,103 to Driehuys et al. entitled xe2x80x9cCoatings for Production of Hyperpolarized Noble Gases.xe2x80x9d Generally stated, this patent describes the use of a modified polymer as a surface coating on physical systems (such as a Pyrex(trademark) container) which contact the hyperpolarized gas to inhibit the decaying effect of the surface of the collection chamber or storage unit.
However, there remains a need to address and reduce dominant and sub-dominant relaxation mechanisms and to decrease the complexity of physical systems required to deliver the hyperpolarized gas to the desired subject. Minimizing the effect of one or more of these factors can increase the life of the product by increasing the duration of the hyperpolarized state. Such an increase is desired so that the hyperpolarized product can retain sufficient polarization to allow effective imaging at delivery when transported over longer transport distances and/or stored for longer time periods from the initial polarization than has been viable previously.
In view of the foregoing, it is an object of the present invention to process and collect hyperpolarized gas in improved resilient containers which are configured to inhibit depolarization in the collected polarized gas and to provide a longer T1 for 3He and 129Xe than has been achieved in the past.
It is another object of the present invention to provide an improved container which can be configured to act as both a transport container and a delivery mechanism to reduce the amount of handling or physical interaction required to deliver the hyperpolarized gas to a subject.
It is a further object of the present invention to provide an improved, relatively non-complex and economical container which can prolong the polarization life of the gas in a container and reduce the amount of polarization lost during storage, transport, and delivery.
It is yet another object of the invention to provide methods, surface materials and containers which will minimize the depolarizing effects of the hyperpolarized state of the gas (especially 3He) attributed to one or more of paramagnetic impurities, oxygen exposure, and surface relaxation.
It is an additional object of the present invention to provide a method to determine the gas solubility in polymers or liquids with respect to hyperpolarized 129Xe or 3He.
These and other objects are satisfied by the present invention which is directed to resilient containers which are configured to reduce surface or contact-induced depolarization by forming an inner contact surface of a first material (of a predetermined thickness) which acts to minimize the associated surface or contact depolarization. In particular, a first aspect of the invention is directed to a container for receiving a quantity of hyperpolarized gas. The container includes at least one wall comprising inner and outer layers configured to define an enclosed chamber for holding a quantity of hyperpolarized gas. The inner layer has a predetermined thickness and an associated relaxivity value which inhibits contact-induced polarization loss of the hyperpolarized gas. The outer layer defines an oxygen shield overlying the inner layer. Of course, the two layers can be integrated into one, if the material chosen acts as a polarization-friendly contact surface and is also resistant to the introduction of oxygen molecules into the chamber of the container. The container also includes a quantity of hyperpolarized noble gas and a port attached to the wall in fluid communication with the chamber for capturing and releasing the hyperpolarized gas therethrough.
Preferably, the container material(s) are selected to result in effective T1""s of greater than 6 hours for 3He and greater than about 4 hours for 129Xe due to the material alone. It is also preferred that the oxygen shield is configured to reduce the migration of oxygen into the container to less than about 5xc3x9710xe2x88x926 amgt/min, and more preferably to less than about 1xc3x9710xe2x88x927 amgt/min. It is additionally preferred that the inner layer thickness (xe2x80x9cLthxe2x80x9d) is at least as thick as the polarization decay length scale (xe2x80x9cLpxe2x80x9d) which can be determined by the equation:
Lp={square root over (TpDp+L )}
where Tp is the noble gas nuclear spin relaxation time in the polymer and Dp is the noble gas diffusion coefficient in the polymer.
Advantageously, using a contact surface which has a thickness which is larger than the polarization decay length scale can minimize or even prevent the hyperpolarized gas from sampling the substrate (the material underlying the first layer). Indeed, for hyperpolarized gases which can have a high diffusion constant (such as 3He), surfaces with polymer coatings substantially thinner than the polarization decay length scale can have a more detrimental effect on the polarization than surfaces having no such coating at all. This is because the polarized gas can be retained within the underlying material and interact with the underlying or substrate material for a longer time, potentially causing more depolarization than if the thin coating is not present.
An additional aspect of the present invention is directed to a container with a wall formed of a single or multiple layers of materials which defines an expandable chamber. The inner surface of the wall is formed of a material which has a low relaxivity value for the (non-toxic) hyperpolarized fluid (hyperpolarized gas which is at least partially dissolved or liquefied) held therein. The wall is configured to define an oxygen shield to inhibit the migration of oxygen into the chamber. The T1 of the hyperpolarized fluid held in the container is greater than about 6 hours.
In a preferred embodiment, the container of the instant invention is configured to receive hyperpolarized 3He and the inner layer is at least 16-20 microns thick. In another preferred embodiment, the container is an expandable polymer bag. Preferably, the polymer bag includes a metallized coating positioned over the polymer which suppresses the migration of oxygen into the polymer and ultimately into the polarized gas holding chamber. In another preferred embodiment, a third layer is added onto the metallized layer (opposite the polymer chamber) for puncture resistance. Advantageously, the captured hyperpolarized gas can be delivered to the inhalation interface of a subject by exerting pressure on the bag to collapse the bag and cause the gases to exit the chamber. This, in turn, removes the requirement for a supplemental delivery mechanism. It is additionally preferred that the container use seals such as O-rings which are substantially free of paramagnetic impurities. The proximate position of the seal with the hyperpolarized gas can make this component a dominant factor in the depolarization of the gas. Accordingly, it is preferred that the seals or O-rings be formed from substantially pure polyolefins such as polyethylene, polypropylene, copolymers and blends thereof. Of course, fillers which are friendly to hyperpolarization can be used (such as substantially pure carbon black and the like). Alternatively, the O-ring or seal can be coated with a surface material such as LDPE or deuterated HDPE or other low-relaxivity and property material and/or also preferably materials which have a low permeability for the hyperpolarized gas held in the chamber. In addition, the container can be configured such that once the gas is captured in the container to isolate a major portion of the hyperpolarized gas in the container away from potentially depolarizing components (such as fittings, valves, and the like) during transport and/or storage.
Similar to the preferred embodiment discussed above, another aspect of the present invention is a multi-layer resilient container for holding hyperpolarized gas. The container comprises a first layer of a first material configured to define an expandable chamber to hold a quantity of hyperpolarized gas therein. Preferably, the first layer has a predetermined thickness sufficient to inhibit surface or contact depolarization of the hyperpolarized gas held therein wherein the first layer material has a relaxivity value xe2x80x9c"Ugr"xe2x80x9d. It is also preferred that the relaxivity value xe2x80x9c"Ugr"xe2x80x9d is less than about 0.0012 cm/min for 3He and less than about 0.001 cm/min for 129Xe. The container also includes a second layer of a second material positioned such that the first layer is between the second layer and the chamber, wherein the first and second layers are concurrently responsive to the application of pressure and one or both of the first and second layers acts as an oxygen shield to suppress oxygen permeability into the chamber.
Additional layers of materials can be positioned intermediate the first layer and the second layer. In one preferred embodiment, hyperpolarized gas has a low relaxivity value in the first layer material and the second layer preferably comprises a material which can shield the migration of the oxygen into the first layer. In another preferred embodiment, the resilient container has a first layer formed of a metal film (which can act both as an oxygen shield and contact surface). In this embodiment, it is preferred that the relaxivity values are less than about 0.0023 cm/min and 0.0008 cm/min for 129Xe and 3He respectively. Stated differently, it is preferred that the hyperpolarized gas have a high mobility on the metal surface or small absorption energy relative to the metal contact surface such that the T1 of the gas in the container approaches  greater than 50% of its theoretical limit.
An additional aspect of the present invention is directed to a method for storing, transporting, and delivering hyperpolarized gas to a target. The method includes introducing a quantity of hyperpolarized gas into a multi-layer resilient container. The container has a wall comprising at least one material which provides an oxygen shield (i.e., is resistant to the transport of oxygen into the container). Preferably, the container is expanded to capture. the quantity of hyperpolarized gas. The container is sealed to contain the hyperpolarized gas therein. The container is transported to a site remote from the hyperpolarization site. The hyperpolarized gas is delivered to a target by compressing the chamber and thereby forcing the hyperpolarized gas to exit therefrom. Preferably, in order to maintain the hyperpolarized state, the container is substantially continuously, from the time of polarization to the delivery, shielded and/or exposed to a proximately maintained homogeneous magnetic field to protect it from undesired external magnetic fields and/or field gradients. It is further preferred that the container be configured to be re-useable (after re-sterilization) to ship additional quantities of hyperpolarized gases.
Similarly, a further aspect of the present invention is configuring single or multi-layer resilient bags as described above with a capillary stem. The capillary stem is configured to restrict the flow of the hyperpolarized gas from the container when the valve is closed. The capillary stem is preferably positioned intermediate the container port and a valve member and, as such, forms a portion of the hyperpolarized gas (or liquid) entrance and exit path. The capillary stem is preferably configured with an inner passage which is sized and configured to inhibit the flow of the hyperpolarized gas and includes a gas contact surface formed of a polarization-friendly material. The capillary stem is preferably operably associated with a valve for the resilient container to allow the gas to be releasably captured and yet protected from any potentially depolarizing affect of the gas when the valve is closed.
Similarly, a further aspect of the present invention is configuring single or multi-layer resilient bags as described above with an isolation means for directing the gas or fluid away from the bag port during transport and storage. As such the isolation means inhibits a major portion of the hyperpolarized gas or fluid from contacting selected components (fittings, valves, O-rings) operably associated with the bag. In a preferred embodiment, the isolation means is provided by a clamp positioned to compress the portion of the bag proximate to the port to inhibit the movement of gas thereabove.
An additional aspect of the present invention is a method for preparing an expandable storage container for receiving a quantity of hyperpolarized gas. The method includes providing a quantity of substantially pure purge gas such as nitrogen or helium (preferably Grade 5 or better) into the hyperpolarized gas container and expanding the hyperpolarized gas container. The container is then collapsed to remove the purge gas. The oxygen in the container walls is outgassed by decreasing the oxygen partial pressure in the container, thereby causing a substantial amount of the oxygen trapped in the walls of the container to migrate into the chamber of the container in the gas phase where it can be removed. Preferably, after the outgassing step, the container is filled with a quantity of storage gas such as nitrogen (again, preferably Grade 5 or better). The gas is introduced into the container at a pressure which reduces the pressure differential across the walls of the container to inhibit further outgassing of the container. Preferably, the container is then stored for future use (the use being spaced apart in time from the point of preconditioning). The storage nitrogen and outgassed oxygen are removed from the container before filling with a quantity of hyperpolarized gas. Preferably, after removal from storage and prior to use, the nitrogen is removed by evacuating the container before filling with a quantity of hyperpolarized gas.
Another aspect of the present invention is directed to a method for determining the hyperpolarized gas (129Xe or 3He) solubility in a (unknown) polymer or a particular fluid. The method includes introducing a first quantity of hyperpolarized noble gas into a container having a known free volume and measuring a first relaxation time of the hyperpolarized gas in the container. A substantially clean sample of desired material is positioned into the container and a second quantity of hyperpolarized noble gas is introduced into the container. A second relaxation time of the second hyperpolarized gas is measured in the container with the sample material. The gas solubility of the sample is determined based on the difference between the two measured relaxation times. The material sample can be a structurally rigid sample (geometrically fixed) with a known geometric surface area/volume which is inserted into the free volume of the chamber or container. Alternatively, the material sample can be a liquid which partially fills chamber.
Advantageously, the methods and containers of the present invention can improve the relaxation time (lengthen T1) of the hyperpolarized gas or liquid or combinations of same held therein. The containers are configured such that the surface contacting the hyperpolarized gas (the hyperpolarized gas contact surface) has a minimum depth or thickness of a low-relaxivity value material relative to the hyperpolarized noble gas. Further, the containers are configured to also inhibit oxygen migration into the gas chamber of the container. In addition, the container itself can define the contact surface by forming the container out of a resilient material such as a metallic or polymer bag. Preferably, the bags are configured to inhibit the hyperpolarized gas from contacting potentially depolarizing components associated with the bag during transport or storage.
The container is preferably a multi-layer container wherein each material layer provides one or more of strength, puncture resistance, and oxygen resistance to the container. Further, at least the inner surface is configured to provide a polarization friendly contact surface. This resilient configuration provides a relatively non-complex container and increased T1""s and can conveniently be re-used. The gas contact surface is preferably formed of either a polymer or a high purity metal.
Additionally, the resilient or collapsible containers can be used to deliver the gas into the patient interface without the need for additional delivery vehicles/equipment. This can reduce the exposure, handling, and physical manipulation of the hyperpolarized gas which, in turn, can increase the polarization life of the hyperpolarized gas. Resilient containers with high purity contact surfaces can be extremely advantageous for both 129Xe and 3He as well as other hyperpolarized gases; however, the expandable (polymer) container and coatings/layers are especially suited for hyperpolarized 3He. Further, the instant invention preferably positions the container with the hyperpolarized gas in a homogenous magnetic field within a shipping container to shield the gas from stray magnetic fields, especially deleterious oscillating fields which can easily dominate other relaxation mechanisms.
Additionally, the present invention can be used to determine the gas solubility in polymers or fluids which in the past has proven difficult and sometimes inaccurate, especially for helium.
Advantageously, one aspect of the present invention now provides a way to model the predictive behavior of surface materials and is particularly suited to determining the relaxation properties of polymers used as contact materials in physical systems used to collect, process, or transport hyperpolarized gases. For example, the present invention successfully provides relaxation properties of various materials (measured and/or calculated). These relaxation values can be used to determine the relaxation time (T1) of hyperpolarized gas in containers corresponding to the solubility of the gas, the surface area of the contact material, and the free gas volume in the container. This information can be advantageously used to extend the hyperpolarized life of the gas in containers over those which were previously achievable in high-volume production systems.
The foregoing and other objects and aspects of the present invention are explained in detail herein.